Peter Nordbeck

Factor XIII Deficiency Causes Cardiac Rupture, Impairs Wound Healing, and Aggravates Cardiac Remodeling in Mice With Myocardial Infarction

Background— Identification of key molecular players in myocardial healing could lead to improved therapies, reduction of scar formation, and heart failure after myocardial infarction (MI). We hypothesized that clotting factor XIII (FXIII), a transglutaminase involved in wound healing, may play an important role in MI given prior clinical and mouse model data. Methods and Results— To determine whether a truly causative relationship existed between FXIII activity and myocardial healing, we prospectively studied myocardial repair in FXIII-deficient mice. All FXIII−/− and FXIII−/+ (FXIII activity <5% and 70%) mice died within 5 days after MI from left ventricular rupture. In contradistinction, FXIII−/− mice that received 5 days of intravenous FXIII replacement therapy had normal survival rates; however, cardiac MRI demonstrated worse left ventricular remodeling in these reconstituted FXIII−/− mice. Using a FXIII-sensitive molecular imaging agent, we found significantly greater FXIII activity in wild-type mice and FXIII−/− mice receiving supplemental FXIII than in FXIII−/− mice (P<0.05). In FXIII−/− but not in reconstituted FXIII−/− mice, histology revealed diminished neutrophil migration into the MI. Reverse transcriptase–polymerase chain reaction studies suggested that the impaired inflammatory response in FXIII−/− mice was independent of intercellular adhesion molecule and lipopolysaccharide-induced CXC chemokine, both important for cell migration. After MI, expression of matrix metalloproteinase-9 was 650% higher and collagen-1 was 53% lower in FXIII−/− mice, establishing an imbalance in extracellular matrix turnover and providing a possible mechanism for the observed cardiac rupture in the FXIII−/− mice. Conclusions— These data suggest that FXIII has an important role in murine myocardial healing after infarction.

Measuring RF-induced currents inside implants: Impact of device configuration on MRI safety of cardiac pacemaker leads

Radiofrequency (RF)‐related heating of cardiac pacemaker leads is a serious concern in magnetic resonance imaging (MRI). Recent investigations suggest such heating to be strongly dependent on an implants position within the surrounding medium, but this issue is currently poorly understood. In this study, phantom measurements of the RF‐induced electric currents inside a pacemaker lead were performed to investigate the impact of the device position and lead configuration on the amount of MRI‐related heating at the lead tip. Seven hundred twenty device position/lead path configurations were investigated. The results show that certain configurations are associated with a highly increased risk to develop MRI‐induced heating, whereas various configurations do not show any significant heating. It was possible to precisely infer implant heating on the basis of current intensity values measured inside a pacemaker lead. Device position and lead configuration relative to the surrounding medium are crucial to the amount of RF‐induced heating in MRI. This indicates that a considerable number of implanted devices may incidentally not develop severe heating in MRI because of their specific configuration in the body. Small variations in configuration can, however, strongly increase the risk for such heating effects, meaning that hazardous situations might appear during MRI. Magn Reson Med, 2009.

PCI Strategies in Patients with Acute Myocardial Infarction and Cardiogenic Shock

Background In patients who have acute myocardial infarction with cardiogenic shock, early revascularization of the culprit artery by means of percutaneous coronary intervention (PCI) improves outcomes. However, the majority of patients with cardiogenic shock have multivessel disease, and whether PCI should be performed immediately for stenoses in nonculprit arteries is controversial. Methods In this multicenter trial, we randomly assigned 706 patients who had multivessel disease, acute myocardial infarction, and cardiogenic shock to one of two initial revascularization strategies: either PCI of the culprit lesion only, with the option of staged revascularization of nonculprit lesions, or immediate multivessel PCI. The primary end point was a composite of death or severe renal failure leading to renal‐replacement therapy within 30 days after randomization. Safety end points included bleeding and stroke. Results At 30 days, the composite primary end point of death or renal‐replacement therapy had occurred in 158 of the 344 patients (45.9%) in the culprit‐lesion‐only PCI group and in 189 of the 341 patients (55.4%) in the multivessel PCI group (relative risk, 0.83; 95% confidence interval [CI], 0.71 to 0.96; P=0.01). The relative risk of death in the culprit‐lesion‐only PCI group as compared with the multivessel PCI group was 0.84 (95% CI, 0.72 to 0.98; P=0.03), and the relative risk of renal‐replacement therapy was 0.71 (95% CI, 0.49 to 1.03; P=0.07). The time to hemodynamic stabilization, the risk of catecholamine therapy and the duration of such therapy, the levels of troponin T and creatine kinase, and the rates of bleeding and stroke did not differ significantly between the two groups. Conclusions Among patients who had multivessel coronary artery disease and acute myocardial infarction with cardiogenic shock, the 30‐day risk of a composite of death or severe renal failure leading to renal‐replacement therapy was lower among those who initially underwent PCI of the culprit lesion only than among those who underwent immediate multivessel PCI. (Funded by the European Union 7th Framework Program and others; CULPRIT‐SHOCK ClinicalTrials.gov number, NCT01927549.)

Spatial distribution of RF-induced E-fields and implant heating in MRI

The purpose of this study was to assess the distribution of RF‐induced E‐fields inside a gel‐filled phantom of the human head and torso and compare the results with the RF‐induced temperature rise at the tip of a straight conductive implant, specifically examining the dependence of the temperature rise on the position of the implant inside the gel. MRI experiments were performed in two different 1.5T MR systems of the same manufacturer. E‐field distribution inside the liquid was assessed using a custom measurement system. The temperature rise at the implant tip was measured in various implant positions and orientations using fluoroptic thermometry. The results show that local E‐field strength in the direction of the implant is a critical factor in RF‐related tissue heating. The actual E‐field distribution, which is dependent on phantom/body properties and the MR‐system employed, must be considered when assessing the effects of RF power deposition in implant safety investigations. Magn Reson Med 60:312–319, 2008.

Minimizing risk of nephrogenic systemic fibrosis in cardiovascular magnetic resonance.

Nephrogenic Systemic Fibrosis is a rare condition appearing only in patients with severe renal impairment or failure and presents with dermal lesions and involvement of internal organs. Although many cases are mild, an estimated 5 % have a progressive debilitating course. To date, there is no known effective treatment thus stressing the necessity of ample prevention measures. An association with the use of Gadolinium based contrast agents (GBCA) makes Nephrogenic Systemic Fibrosis a potential side effect of contrast enhanced magnetic resonance imaging and offers the opportunity for prevention by limiting use of gadolinium based contrast agents in renal failure patients. In itself toxic, Gadolinium is embedded into chelates that allow its safe use as a contrast agent. One NSF theory is that Gadolinium chelates distribute into the extracellular fluid compartment and set Gadolinium ions free, depending on multiple factors among which the duration of chelates exposure is directly related to the renal function. Major medical societies both in Europe and in North America have developed guidelines for the usage of GBCA. Since the establishment of these guidelines and the increased general awareness of this condition, the occurrence of NSF has been nearly eliminated. Giving an overview over the current knowledge of NSF pathobiochemistry, pathogenesis and treatment options this review focuses on the guidelines of the European Medicines Agency, the European Society of Urogenital Radiology, the FDA and the American College of Radiology from 2008 up to 2011 and the transfer of this knowledge into every day practice.

Magnetic resonance imaging safety in pacemaker and implantable cardioverter defibrillator patients: how far have we come?

Magnetic resonance imaging (MRI) has long been regarded a general contraindication in patients with cardiovascular implanted electronic devices such as cardiac pacemakers or cardioverter defibrillators (ICDs) due to the risk of severe complications and even deaths caused by interactions of the magnetic resonance (MR) surrounding and the electric devices. Over the last decade, a better understanding of the underlying mechanisms responsible for such potentially life-threatening complications as well as technical advances have allowed an increasing number of pacemaker and ICD patients to safely undergo MRI. This review lists the key findings from basic research and clinical trials over the last 20 years, and discusses the impact on current day clinical practice. With ‘MR-conditional’ devices being the new standard of care, MRI in pacemaker and ICD patients has been adopted to clinical routine today. However, specific precautions and specifications of these devices should be carefully followed if possible, to avoid patient risks which might appear with new MR technology and further increasing indications and patient numbers.

Conditional Overexpression of Neuronal Nitric Oxide Synthase Is Cardioprotective in Ischemia/Reperfusion

Background— We previously demonstrated that conditional overexpression of neuronal nitric oxide synthase (nNOS) inhibited L-type Ca2+ channels and decreased myocardial contractility. However, nNOS has multiple targets within the cardiac myocyte. We now hypothesize that nNOS overexpression is cardioprotective after ischemia/reperfusion because of inhibition of mitochondrial function and a reduction in reactive oxygen species generation. Methods and Results— Ischemia/reperfusion injury in wild-type mice resulted in nNOS accumulation in the mitochondria. Similarly, transgenic nNOS overexpression caused nNOS abundance in mitochondria. nNOS translocation into the mitochondria was dependent on heat shock protein 90. Ischemia/reperfusion experiments in isolated hearts showed a cardioprotective effect of nNOS overexpression. Infarct size in vivo was also significantly reduced. nNOS overexpression also caused a significant increase in mitochondrial nitrite levels accompanied by a decrease of cytochrome c oxidase activity. Accordingly, O2 consumption in isolated heart muscle strips was decreased in nNOS-overexpressing nNOS+/&agr;MHC-tTA+ mice already under resting conditions. Additionally, we found that the reactive oxygen species concentration was significantly decreased in hearts of nNOS-overexpressing nNOS+/&agr;MHC-tTA+ mice compared with noninduced nNOS+/&agr;MHC-tTA+ animals. Conclusion— We demonstrated that conditional transgenic overexpression of nNOS resulted in myocardial protection after ischemia/reperfusion injury. Besides a reduction in reactive oxygen species generation, this might be caused by nitrite-mediated inhibition of mitochondrial function, which reduced myocardial oxygen consumption already under baseline conditions.

Feasibility of Real-Time MRI With a Novel Carbon Catheter for Interventional Electrophysiology

Background—Cardiac MRI offers 3D real-time imaging with unsurpassed soft tissue contrast without x-ray exposure. To minimize safety concerns and imaging artifacts in MR-guided interventional electrophysiology (EP), we aimed at developing a setup including catheters for ablation therapy based on carbon technology. Methods and Results—The setup, including a steerable carbon catheter, was tested for safety, image distortion, and feasibility of diagnostic EP studies and radiofrequency ablation at 1.5 T. MRI was performed in 3 different 1.5-T whole-body scanners using various receive coils and pulse sequences. To assess unintentional heating of the catheters by radiofrequency pulses of the MR scanner in vitro, a fluoroptic thermometry system was used to record heating at the catheter tip. Programmed stimulation and ablation therapy was performed in 8 pigs. There was no significant heating of the carbon catheters while using short, repetitive radiofrequency pulses from the MR system. Because there was no image distortion when using the carbon catheters, exact targeting of the lesion sites was possible. Both atrial and ventricular radiofrequency ablation procedures including atrioventricular node modulation were performed successfully in the scanner. Potential complications such as pericardial effusion after intentional perforation of the right ventricular free wall during ablation could be monitored in real time as well. Conclusion—We describe a newly developed EP technology for interventional electrophysiology based on carbon catheters. The feasibility of this approach was demonstrated by safety testing and performing EP studies and ablation therapy with carbon catheters in the MRI environment.

Feasibility of Real Time Magnetic Resonance Imaging with a Novel Carbon Catheter for Interventional Electrophysiology

Background—Cardiac MRI offers 3D real-time imaging with unsurpassed soft tissue contrast without x-ray exposure. To minimize safety concerns and imaging artifacts in MR-guided interventional electrophysiology (EP), we aimed at developing a setup including catheters for ablation therapy based on carbon technology. Methods and Results—The setup, including a steerable carbon catheter, was tested for safety, image distortion, and feasibility of diagnostic EP studies and radiofrequency ablation at 1.5 T. MRI was performed in 3 different 1.5-T whole-body scanners using various receive coils and pulse sequences. To assess unintentional heating of the catheters by radiofrequency pulses of the MR scanner in vitro, a fluoroptic thermometry system was used to record heating at the catheter tip. Programmed stimulation and ablation therapy was performed in 8 pigs. There was no significant heating of the carbon catheters while using short, repetitive radiofrequency pulses from the MR system. Because there was no image distortion when using the carbon catheters, exact targeting of the lesion sites was possible. Both atrial and ventricular radiofrequency ablation procedures including atrioventricular node modulation were performed successfully in the scanner. Potential complications such as pericardial effusion after intentional perforation of the right ventricular free wall during ablation could be monitored in real time as well. Conclusion—We describe a newly developed EP technology for interventional electrophysiology based on carbon catheters. The feasibility of this approach was demonstrated by safety testing and performing EP studies and ablation therapy with carbon catheters in the MRI environment.

Impact of imaging landmark on the risk of MRI‐related heating near implanted medical devices like cardiac pacemaker leads

Implanted medical devices such as cardiac pacemakers pose a potential hazard in magnetic resonance imaging. Electromagnetic fields have been shown to cause severe radio frequency‐induced tissue heating in some cases. Imaging exclusion zones have been proposed as an instrument to reduce patient risk. The purpose of this study was to further assess the impact of the imaging landmark on the risk for unintended implant heating by measuring the radio frequency‐induced electric fields in a body phantom under several imaging conditions at 1.5T. The results show that global radio frequency‐induced coupling is highest with the torso centered along the superior–inferior direction of the transmit coil. The induced E‐fields inside the body shift when changing body positioning, reducing both global and local radio frequency coupling if body and/or conductive implant are moved out from the transmit coil center along the z‐direction. Adequate selection of magnetic resonance imaging landmark can significantly reduce potential hazards in patients with implanted medical devices. Magn Reson Med, 2010.